
Glycolysis is the
metabolic pathway
In biochemistry, a metabolic pathway is a linked series of chemical reactions occurring within a cell (biology), cell. The reactants, products, and Metabolic intermediate, intermediates of an enzymatic reaction are known as metabolites, which are ...
that converts
glucose
Glucose is a sugar with the Chemical formula#Molecular formula, molecular formula , which is often abbreviated as Glc. It is overall the most abundant monosaccharide, a subcategory of carbohydrates. It is mainly made by plants and most algae d ...
() into
pyruvate
Pyruvic acid (CH3COCOOH) is the simplest of the alpha-keto acids, with a carboxylic acid and a ketone functional group. Pyruvate, the conjugate base, CH3COCOO−, is an intermediate in several metabolic pathways throughout the cell.
Pyruvic ...
and, in most organisms, occurs in the liquid part of cells (the
cytosol
The cytosol, also known as cytoplasmic matrix or groundplasm, is one of the liquids found inside cells ( intracellular fluid (ICF)). It is separated into compartments by membranes. For example, the mitochondrial matrix separates the mitochondri ...
). The
free energy released in this process is used to form the high-energy molecules
adenosine triphosphate
Adenosine triphosphate (ATP) is a nucleoside triphosphate that provides energy to drive and support many processes in living cell (biology), cells, such as muscle contraction, nerve impulse propagation, and chemical synthesis. Found in all known ...
(ATP) and
reduced nicotinamide adenine dinucleotide (NADH). Glycolysis is a sequence of ten reactions catalyzed by
enzyme
An enzyme () is a protein that acts as a biological catalyst by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different mol ...
s.

The wide occurrence of glycolysis in other species indicates that it is an ancient metabolic pathway. Indeed, the reactions that make up glycolysis and its parallel pathway, the
pentose phosphate pathway
The pentose phosphate pathway (also called the phosphogluconate pathway and the hexose monophosphate shunt or HMP shunt) is a metabolic pathway parallel to glycolysis. It generates NADPH and pentoses (five-carbon sugars) as well as ribose 5-ph ...
, can occur in the
oxygen-free conditions of the
Archean
The Archean ( , also spelled Archaean or Archæan), in older sources sometimes called the Archaeozoic, is the second of the four geologic eons of Earth's history of Earth, history, preceded by the Hadean Eon and followed by the Proterozoic and t ...
oceans, also in the absence of enzymes, catalyzed by metal ions, meaning this is a plausible prebiotic pathway for
abiogenesis
Abiogenesis is the natural process by which life arises from non-living matter, such as simple organic compounds. The prevailing scientific hypothesis is that the transition from non-living to living entities on Earth was not a single even ...
.
The most common type of glycolysis is the ''Embden–Meyerhof–Parnas (EMP) pathway'', which was discovered by
Gustav Embden,
Otto Meyerhof, and
Jakub Karol Parnas
Jakub Karol Parnas, also known as Yakov Oskarovich Parnas (; January 16, 1884 – January 29, 1949) was a prominent Polish–Soviet biochemist who contributed to the discovery of the Embden–Meyerhof–Parnas pathway, together with Otto F ...
. Glycolysis also refers to other pathways, such as the ''
Entner–Doudoroff pathway'' and various heterofermentative and homofermentative pathways. However, the discussion here will be limited to the Embden–Meyerhof–Parnas pathway.
The glycolysis pathway can be separated into two phases:
# Investment phase – wherein ATP is consumed
# Yield phase – wherein more ATP is produced than originally consumed
Overview
The overall reaction of glycolysis is:

The use of symbols in this equation makes it appear unbalanced with respect to oxygen atoms, hydrogen atoms, and charges. Atom balance is maintained by the two phosphate (P
i) groups:
* Each exists in the form of a
hydrogen phosphate anion (), dissociating to contribute overall
* Each liberates an oxygen atom when it binds to an
adenosine diphosphate
Adenosine diphosphate (ADP), also known as adenosine pyrophosphate (APP), is an important organic compound in metabolism and is essential to the flow of energy in living cells. ADP consists of three important structural components: a sugar backbon ...
(ADP) molecule, contributing 2O overall
Charges are balanced by the difference between ADP and ATP. In the cellular environment, all three hydroxyl groups of ADP dissociate into −O
− and H
+, giving ADP
3−, and this ion tends to exist in an ionic bond with Mg
2+, giving ADPMg
−. ATP behaves identically except that it has four hydroxyl groups, giving ATPMg
2−. When these differences along with the true charges on the two phosphate groups are considered together, the net charges of −4 on each side are balanced.
In high-oxygen (aerobic) conditions, eukaryotic cells can continue from glycolysis to metabolise the pyruvate through the
citric acid cycle
The citric acid cycle—also known as the Krebs cycle, Szent–Györgyi–Krebs cycle, or TCA cycle (tricarboxylic acid cycle)—is a series of chemical reaction, biochemical reactions that release the energy stored in nutrients through acetyl-Co ...
or the
electron transport chain
An electron transport chain (ETC) is a series of protein complexes and other molecules which transfer electrons from electron donors to electron acceptors via redox reactions (both reduction and oxidation occurring simultaneously) and couples th ...
to produce significantly more ATP.
Importantly, under low-oxygen (anaerobic) conditions, glycolysis is the only biochemical pathway in eukaryotes that can generate ATP, and, for many anaerobic respiring organisms the most important producer of ATP. Therefore, many organisms have evolved
fermentation
Fermentation is a type of anaerobic metabolism which harnesses the redox potential of the reactants to make adenosine triphosphate (ATP) and organic end products. Organic molecules, such as glucose or other sugars, are catabolized and reduce ...
pathways to recycle NAD
+ to continue glycolysis to produce ATP for survival. These pathways include
ethanol fermentation
Ethanol fermentation, also called alcoholic fermentation, is a biological process which converts sugars such as glucose, fructose, and sucrose into cellular energy, producing ethanol and carbon dioxide as by-products. Because yeasts perform this ...
and
lactic acid fermentation
Lactic acid fermentation is a metabolic process by which glucose or other hexose, six-carbon sugars (also, disaccharides of six-carbon sugars, e.g. sucrose or lactose) are converted into cellular energy and the metabolite lactic acid, lactate, w ...
.
History
The modern understanding of the pathway of glycolysis took almost 100 years to fully learn.
The combined results of many smaller experiments were required to understand the entire pathway.
The first steps in understanding glycolysis began in the 19th century. For economic reasons, the French wine industry sought to investigate why wine sometimes turned distasteful, instead of fermenting into alcohol. The French scientist
Louis Pasteur
Louis Pasteur (, ; 27 December 1822 – 28 September 1895) was a French chemist, pharmacist, and microbiologist renowned for his discoveries of the principles of vaccination, Fermentation, microbial fermentation, and pasteurization, the la ...
researched this issue during the 1850s. His experiments showed that alcohol fermentation occurs by the action of living
microorganism
A microorganism, or microbe, is an organism of microscopic scale, microscopic size, which may exist in its unicellular organism, single-celled form or as a Colony (biology)#Microbial colonies, colony of cells. The possible existence of unseen ...
s, yeasts, and that glucose consumption decreased under aerobic conditions (the
Pasteur effect
The Pasteur effect describes how available oxygen inhibits ethanol fermentation, driving yeast to switch toward aerobic respiration for increased generation of the energy carrier adenosine triphosphate (ATP). More generally, in the medical liter ...
).

The component steps of glycolysis were first analysed by the non-cellular fermentation experiments of
Eduard Buchner
Eduard Buchner (; 20 May 1860 – 13 August 1917) was a German chemist and Zymurgy, zymologist, awarded the 1907 Nobel Prize in Chemistry for his work on fermentation (biochemistry), fermentation.
Biography
Early years
Buchner was born in Mun ...
during the 1890s. Buchner demonstrated that the conversion of glucose to ethanol was possible using a non-living extract of yeast, due to the action of
enzyme
An enzyme () is a protein that acts as a biological catalyst by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different mol ...
s in the extract.
This experiment not only revolutionized biochemistry, but also allowed later scientists to analyze this pathway in a more controlled laboratory setting. In a series of experiments (1905–1911), scientists
Arthur Harden and
William Young discovered more pieces of glycolysis.
They discovered the regulatory effects of ATP on glucose consumption during alcohol fermentation. They also shed light on the role of one compound as a glycolysis intermediate: fructose 1,6-bisphosphate.
The elucidation of fructose 1,6-bisphosphate was accomplished by measuring levels when yeast juice was incubated with glucose. production increased rapidly then slowed down. Harden and Young noted that this process would restart if an inorganic phosphate (Pi) was added to the mixture. Harden and Young deduced that this process produced organic phosphate esters, and further experiments allowed them to extract fructose diphosphate (F-1,6-DP).
Arthur Harden and
William Young along with Nick Sheppard determined, in a second experiment, that a heat-sensitive high-molecular-weight subcellular fraction (the enzymes) and a heat-insensitive low-molecular-weight cytoplasm fraction (ADP, ATP and NAD
+ and other
cofactors) are required together for fermentation to proceed. This experiment begun by observing that dialyzed (purified) yeast juice could not ferment or even create a sugar phosphate. This mixture was rescued with the addition of undialyzed yeast extract that had been boiled. Boiling the yeast extract renders all proteins inactive (as it denatures them). The ability of boiled extract plus dialyzed juice to complete fermentation suggests that the cofactors were non-protein in character.

In the 1920s
Otto Meyerhof was able to link together some of the many individual pieces of glycolysis discovered by Buchner, Harden, and Young. Meyerhof and his team were able to extract different glycolytic enzymes from
muscle tissue
Muscle is a soft tissue, one of the four basic types of animal tissue. There are three types of muscle tissue in vertebrates: skeletal muscle, cardiac muscle, and smooth muscle. Muscle tissue gives skeletal muscles the ability to contract. ...
, and combine them to artificially create the pathway from glycogen to lactic acid.
In one paper, Meyerhof and scientist Renate Junowicz-Kockolaty investigated the reaction that splits fructose 1,6-diphosphate into the two triose phosphates. Previous work proposed that the split occurred via 1,3-diphosphoglyceraldehyde plus an oxidizing enzyme and cozymase. Meyerhoff and Junowicz found that the equilibrium constant for the isomerase and aldoses reaction were not affected by inorganic phosphates or any other cozymase or oxidizing enzymes. They further removed diphosphoglyceraldehyde as a possible intermediate in glycolysis.
With all of these pieces available by the 1930s,
Gustav Embden proposed a detailed, step-by-step outline of that pathway we now know as glycolysis. The biggest difficulties in determining the intricacies of the pathway were due to the very short lifetime and low steady-state concentrations of the intermediates of the fast glycolytic reactions. By the 1940s, Meyerhof, Embden and many other biochemists had finally completed the puzzle of glycolysis.
The understanding of the isolated pathway has been expanded in the subsequent decades, to include further details of its regulation and integration with other metabolic pathways.
Sequence of reactions
Summary of reactions
Preparatory phase
The first five steps of Glycolysis are regarded as the preparatory (or investment) phase, since they consume energy to convert the glucose into two three-carbon sugar phosphates
(
G3P).
Once glucose enters the cell, the first step is phosphorylation of glucose by a family of enzymes called
hexokinase
A hexokinase is an enzyme that irreversibly phosphorylates hexoses (six-carbon sugars), forming hexose phosphate. In most organisms, glucose is the most important substrate for hexokinases, and glucose-6-phosphate is the most important p ...
s to form glucose 6-phosphate (G6P). This reaction consumes ATP, but it acts to keep the glucose concentration inside the cell low, promoting continuous transport of blood glucose into the cell through the plasma membrane transporters. In addition, phosphorylation blocks the glucose from leaking out – the cell lacks transporters for G6P, and free diffusion out of the cell is prevented due to the charged nature of G6P. Glucose may alternatively be formed from the
phosphorolysis or
hydrolysis
Hydrolysis (; ) is any chemical reaction in which a molecule of water breaks one or more chemical bonds. The term is used broadly for substitution reaction, substitution, elimination reaction, elimination, and solvation reactions in which water ...
of intracellular starch or glycogen.
In
animal
Animals are multicellular, eukaryotic organisms in the Biology, biological Kingdom (biology), kingdom Animalia (). With few exceptions, animals heterotroph, consume organic material, Cellular respiration#Aerobic respiration, breathe oxygen, ...
s, an
isozyme
In biochemistry, isozymes (also known as isoenzymes or more generally as multiple forms of enzymes) are enzymes that differ in amino acid sequence but catalyze the same chemical reaction. Isozymes usually have different kinetic parameters (e.g. di ...
of hexokinase called
glucokinase
Glucokinase () is an enzyme that facilitates phosphorylation of glucose to glucose-6-phosphate. Glucokinase is expressed in cells of the liver and pancreas of humans and most other vertebrates. In each of these organs it plays an important ro ...
is also used in the liver, which has a much lower affinity for glucose (K
m in the vicinity of normal glycemia), and differs in regulatory properties. The different substrate affinity and alternate regulation of this enzyme are a reflection of the role of the liver in maintaining blood sugar levels.
''Cofactors:'' Mg
2+
G6P is then rearranged into
fructose 6-phosphate
Fructose 6-phosphate (sometimes called the Neuberg ester) is a derivative of fructose, which has been phosphorylated at the 6-hydroxy group. It is one of several possible fructosephosphates. The β-D-form of this compound is very common in cells ...
(F6P) by
glucose phosphate isomerase.
Fructose
Fructose (), or fruit sugar, is a Ketose, ketonic monosaccharide, simple sugar found in many plants, where it is often bonded to glucose to form the disaccharide sucrose. It is one of the three dietary monosaccharides, along with glucose and gal ...
can also enter the glycolytic pathway by phosphorylation at this point.
The change in structure is an isomerization, in which the G6P has been converted to F6P. The reaction requires an enzyme, phosphoglucose isomerase, to proceed. This reaction is freely reversible under normal cell conditions. However, it is often driven forward because of a low concentration of F6P, which is constantly consumed during the next step of glycolysis. Under conditions of high F6P concentration, this reaction readily runs in reverse. This phenomenon can be explained through
Le Chatelier's Principle
In chemistry, Le Chatelier's principle (pronounced or ) is a principle used to predict the effect of a change in conditions on chemical equilibrium. Other names include Chatelier's principle, Braun–Le Chatelier principle, Le Chatelier–Braun p ...
. Isomerization to a keto sugar is necessary for carbanion stabilization in the fourth reaction step (below).
The energy expenditure of another ATP in this step is justified in 2 ways: The glycolytic process (up to this step) becomes irreversible, and the energy supplied destabilizes the molecule. Because the reaction catalyzed by
phosphofructokinase 1 (PFK-1) is coupled to the hydrolysis of ATP (an energetically favorable step) it is, in essence, irreversible, and a different pathway must be used to do the reverse conversion during
gluconeogenesis
Gluconeogenesis (GNG) is a metabolic pathway that results in the biosynthesis of glucose from certain non-carbohydrate carbon substrates. It is a ubiquitous process, present in plants, animals, fungi, bacteria, and other microorganisms. In verte ...
. This makes the reaction a key regulatory point (see below).
Furthermore, the second phosphorylation event is necessary to allow the formation of two charged groups (rather than only one) in the subsequent step of glycolysis, ensuring the prevention of free diffusion of substrates out of the cell.
The same reaction can also be catalyzed by
pyrophosphate-dependent phosphofructokinase (PFP or PPi-PFK), which is found in most plants, some bacteria, archea, and protists, but not in animals. This enzyme uses pyrophosphate (PPi) as a phosphate donor instead of ATP. It is a reversible reaction, increasing the flexibility of glycolytic metabolism. A rarer ADP-dependent PFK enzyme variant has been identified in archaean species.
''Cofactors:'' Mg
2+
Destabilizing the molecule in the previous reaction allows the hexose ring to be split by
aldolase
Fructose-bisphosphate aldolase (), often just aldolase, is an enzyme catalyzing a reversible reaction that splits the aldol, fructose 1,6-bisphosphate, into the triose phosphates dihydroxyacetone phosphate (DHAP) and glyceraldehyde 3-phosphat ...
into two triose sugars:
dihydroxyacetone phosphate
Dihydroxyacetone phosphate (DHAP, also glycerone phosphate in older texts) is the anion with the formula HOCH2C(O)CH2OPO32-. This anion is involved in many metabolic pathways, including the Calvin cycle in plants and glycolysis.Nelson, D. L.; Co ...
(a ketose), and
glyceraldehyde 3-phosphate
Glyceraldehyde 3-phosphate, also known as triose phosphate or 3-phosphoglyceraldehyde and abbreviated as G3P, GA3P, GADP, GAP, TP, GALP or PGAL, is a metabolite that occurs as an intermediate in several central pathways of all organisms.Nelson, D ...
(an aldose). There are two classes of aldolases: class I aldolases, present in animals and plants, and class II aldolases, present in fungi and bacteria; the two classes use different mechanisms in cleaving the ketose ring.
Electrons delocalized in the carbon-carbon bond cleavage associate with the alcohol group. The resulting carbanion is stabilized by the structure of the carbanion itself via resonance charge distribution and by the presence of a charged ion prosthetic group.
Triosephosphate isomerase rapidly interconverts dihydroxyacetone phosphate with
glyceraldehyde 3-phosphate
Glyceraldehyde 3-phosphate, also known as triose phosphate or 3-phosphoglyceraldehyde and abbreviated as G3P, GA3P, GADP, GAP, TP, GALP or PGAL, is a metabolite that occurs as an intermediate in several central pathways of all organisms.Nelson, D ...
(GADP) that proceeds further into glycolysis. This is advantageous, as it directs dihydroxyacetone phosphate down the same pathway as glyceraldehyde 3-phosphate, simplifying regulation.
Pay-off phase
The second half of glycolysis is known as the pay-off phase, characterised by a net gain of the energy-rich molecules ATP and NADH.
Since glucose leads to two triose sugars in the preparatory phase, each reaction in the pay-off phase occurs twice per glucose molecule. This yields 2 NADH molecules and 4 ATP molecules, leading to a net gain of 2 NADH molecules and 2 ATP molecules from the glycolytic pathway per glucose.
The aldehyde groups of the triose sugars are
oxidised, and
inorganic phosphate is added to them, forming
1,3-bisphosphoglycerate.
The hydrogen is used to reduce two molecules of
NAD+, a hydrogen carrier, to give NADH + H
+ for each triose.
Hydrogen atom balance and charge balance are both maintained because the phosphate (P
i) group actually exists in the form of a
hydrogen phosphate anion (),
which dissociates to contribute the extra H
+ ion and gives a net charge of −3 on both sides.
Here,
arsenate
The arsenate is an ion with the chemical formula . Bonding in arsenate consists of a central arsenic atom, with oxidation state +5, double bonded to one oxygen atom and single bonded to a further three oxygen atoms. The four oxygen atoms orien ...
(), an anion akin to inorganic phosphate may replace phosphate as a substrate to form 1-arseno-3-phosphoglycerate. This, however, is unstable and readily hydrolyzes to form
3-phosphoglycerate, the intermediate in the next step of the pathway. As a consequence of bypassing this step, the molecule of ATP generated from
1–3 bisphosphoglycerate in the next reaction will not be made, even though the reaction proceeds. As a result, arsenate is an uncoupler of glycolysis.
This step is the enzymatic transfer of a phosphate group from
1,3-bisphosphoglycerate to ADP by
phosphoglycerate kinase, forming ATP and
3-phosphoglycerate. At this step, glycolysis has reached the break-even point: 2 molecules of ATP were consumed, and 2 new molecules have now been synthesized. This step, one of the two
substrate-level phosphorylation
Substrate-level phosphorylation is a metabolism reaction that results in the production of ATP or GTP supported by the energy released from another high-energy bond that leads to phosphorylation of ADP or GDP to ATP or GTP (note that the rea ...
steps, requires ADP; thus, when the cell has plenty of ATP (and little ADP), this reaction does not occur. Because ATP decays relatively quickly when it is not metabolized, this is an important regulatory point in the glycolytic pathway.
ADP actually exists as ADPMg
−, and ATP as ATPMg
2−, balancing the charges at −5 both sides.
''Cofactors:'' Mg
2+
Phosphoglycerate mutase
:''This enzyme is not to be confused with Bisphosphoglycerate mutase which catalyzes the conversion of 1,3-bisphosphoglycerate to 2,3-bisphosphoglycerate.''
Phosphoglycerate mutase (PGM) is any enzyme that catalyzes step 8 of glycolysis ...
isomerises
3-phosphoglycerate into
2-phosphoglycerate.
Enolase
Phosphopyruvate hydratase, usually known as enolase, is a metalloenzyme () that catalyses the conversion of 2-phosphoglycerate (2-PG) to phosphoenolpyruvate (PEP), the ninth and penultimate step of glycolysis. The chemical reaction is:
:2-ph ...
next converts
2-phosphoglycerate to
phosphoenolpyruvate
Phosphoenolpyruvate (2-phosphoenolpyruvate, PEP) is the carboxylic acid derived from the enol of pyruvate and a phosphate anion. It exists as an anion. PEP is an important intermediate in biochemistry. It has the high-energy phosphate, highest-e ...
. This reaction is an elimination reaction involving an
E1cB mechanism.
''Cofactors:'' 2 Mg
2+, one "conformational" ion to coordinate with the carboxylate group of the substrate, and one "catalytic" ion that participates in the dehydration.
A final
substrate-level phosphorylation
Substrate-level phosphorylation is a metabolism reaction that results in the production of ATP or GTP supported by the energy released from another high-energy bond that leads to phosphorylation of ADP or GDP to ATP or GTP (note that the rea ...
now forms a molecule of
pyruvate
Pyruvic acid (CH3COCOOH) is the simplest of the alpha-keto acids, with a carboxylic acid and a ketone functional group. Pyruvate, the conjugate base, CH3COCOO−, is an intermediate in several metabolic pathways throughout the cell.
Pyruvic ...
and a molecule of ATP by means of the enzyme
pyruvate kinase
Pyruvate kinase is the enzyme involved in the last step of glycolysis. It catalyzes the transfer of a phosphate group from phosphoenolpyruvate (PEP) to adenosine diphosphate (ADP), yielding one molecule of pyruvate and one molecule of ATP. Pyruv ...
. This serves as an additional regulatory step, similar to the phosphoglycerate kinase step.
''Cofactors:'' Mg
2+
Biochemical logic
The existence of more than one point of regulation indicates that intermediates between those points enter and leave the glycolysis pathway by other processes. For example, in the first regulated step,
hexokinase
A hexokinase is an enzyme that irreversibly phosphorylates hexoses (six-carbon sugars), forming hexose phosphate. In most organisms, glucose is the most important substrate for hexokinases, and glucose-6-phosphate is the most important p ...
converts glucose into glucose-6-phosphate. Instead of continuing through the glycolysis pathway, this intermediate can be converted into glucose storage molecules, such as
glycogen
Glycogen is a multibranched polysaccharide of glucose that serves as a form of energy storage in animals, fungi, and bacteria. It is the main storage form of glucose in the human body.
Glycogen functions as one of three regularly used forms ...
or
starch
Starch or amylum is a polymeric carbohydrate consisting of numerous glucose units joined by glycosidic bonds. This polysaccharide is produced by most green plants for energy storage. Worldwide, it is the most common carbohydrate in human diet ...
. The reverse reaction, breaking down, e.g., glycogen, produces mainly glucose-6-phosphate; very little free glucose is formed in the reaction. The glucose-6-phosphate so produced can enter glycolysis ''after'' the first control point.
In the second regulated step (the third step of glycolysis),
phosphofructokinase converts fructose-6-phosphate into fructose-1,6-bisphosphate, which then is converted into glyceraldehyde-3-phosphate and dihydroxyacetone phosphate. The dihydroxyacetone phosphate can be removed from glycolysis by conversion into glycerol-3-phosphate, which can be used to form triglycerides. Conversely,
triglyceride
A triglyceride (from '' tri-'' and '' glyceride''; also TG, triacylglycerol, TAG, or triacylglyceride) is an ester derived from glycerol and three fatty acids.
Triglycerides are the main constituents of body fat in humans and other vertebrates ...
s can be broken down into fatty acids and glycerol; the latter, in turn, can be
converted into dihydroxyacetone phosphate, which can enter glycolysis ''after'' the second control point.
Free energy changes
The change in free energy, Δ''G'', for each step in the glycolysis pathway can be calculated using Δ''G'' = Δ''G''°′ + ''RT''ln ''Q'', where ''Q'' is the
reaction quotient
In chemical thermodynamics, the reaction quotient (''Q''r or just ''Q'') is a dimensionless quantity that provides a measurement of the relative amounts of products and reactants present in a reaction mixture for a reaction with well-defined overal ...
. This requires knowing the concentrations of the
metabolites
In biochemistry, a metabolite is an intermediate or end product of metabolism.
The term is usually used for small molecules. Metabolites have various functions, including fuel, structure, signaling, stimulatory and inhibitory effects on enzymes, c ...
. All of these values are available for
erythrocytes
Red blood cells (RBCs), referred to as erythrocytes (, with -''cyte'' translated as 'cell' in modern usage) in academia and medical publishing, also known as red cells, erythroid cells, and rarely haematids, are the most common type of blood cel ...
, with the exception of the concentrations of NAD
+ and NADH. The ratio of
NAD+ to NADH in the cytoplasm is approximately 1000, which makes the oxidation of glyceraldehyde-3-phosphate (step 6) more favourable.
Using the measured concentrations of each step, and the standard free energy changes, the actual free energy change can be calculated. (Neglecting this is very common—the delta G of ATP hydrolysis in cells is not the standard free energy change of ATP hydrolysis quoted in textbooks).
From measuring the physiological concentrations of metabolites in an erythrocyte it seems that about seven of the steps in glycolysis are in equilibrium for that cell type. Three of the steps—the ones with large negative free energy changes—are not in equilibrium and are referred to as ''irreversible''; such steps are often subject to regulation.
Step 5 in the figure is shown behind the other steps, because that step is a side-reaction that can decrease or increase the concentration of the intermediate glyceraldehyde-3-phosphate. That compound is converted to dihydroxyacetone phosphate by the enzyme triose phosphate isomerase, which is a
catalytically perfect enzyme; its rate is so fast that the reaction can be assumed to be in equilibrium. The fact that Δ''G'' is not zero indicates that the actual concentrations in the erythrocyte are not accurately known.
Regulation
The enzymes that catalyse glycolysis are regulated via a range of biological mechanisms in order to control overall
flux
Flux describes any effect that appears to pass or travel (whether it actually moves or not) through a surface or substance. Flux is a concept in applied mathematics and vector calculus which has many applications in physics. For transport phe ...
though the pathway. This is vital for both
homeostatsis in a static environment, and
metabolic adaptation to a changing environment or need. The details of regulation for some enzymes are highly conserved between species, whereas others vary widely.
# Gene Expression: Firstly, the cellular concentrations of glycolytic enzymes are modulated via
regulation of gene expression
Regulation of gene expression, or gene regulation, includes a wide range of mechanisms that are used by cells to increase or decrease the production of specific gene products (protein or RNA). Sophisticated programs of gene expression are wide ...
via
transcription factors
In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription of genetic information from DNA to messenger RNA, by binding to a specific DNA sequence. The fun ...
, with several glycolysis enzymes themselves acting as
regulatory protein kinases in the nucleus.
#
Allosteric inhibition and activation by metabolites: In particular
end-product inhibition of regulated enzymes by metabolites such as ATP serves as negative feedback regulation of the pathway.
# Allosteric inhibition and activation by
Protein-protein interactions (PPI). Indeed, some proteins interact with and regulate multiple glycolytic enzymes.
#
Post-translational modification (PTM). In particular, phosphorylation and dephosphorylation is a key mechanism of regulation of pyruvate kinase in the liver.
#
Localization
Regulation by insulin in animals
In animals, regulation of blood glucose levels by the pancreas in conjunction with the liver is a vital part of
homeostasis
In biology, homeostasis (British English, British also homoeostasis; ) is the state of steady internal physics, physical and chemistry, chemical conditions maintained by organism, living systems. This is the condition of optimal functioning fo ...
. The
beta cells in the
pancreatic islets
The pancreatic islets or islets of Langerhans are the regions of the pancreas that contain its endocrine (hormone-producing) cells, discovered in 1869 by German pathological anatomist Paul Langerhans. The pancreatic islets constitute 1–2% o ...
are sensitive to the blood glucose concentration.
A rise in the blood glucose concentration causes them to release
insulin
Insulin (, from Latin ''insula'', 'island') is a peptide hormone produced by beta cells of the pancreatic islets encoded in humans by the insulin (''INS)'' gene. It is the main Anabolism, anabolic hormone of the body. It regulates the metabol ...
into the blood, which has an effect particularly on the liver, but also on
fat
In nutrition science, nutrition, biology, and chemistry, fat usually means any ester of fatty acids, or a mixture of such chemical compound, compounds, most commonly those that occur in living beings or in food.
The term often refers specif ...
and
muscle
Muscle is a soft tissue, one of the four basic types of animal tissue. There are three types of muscle tissue in vertebrates: skeletal muscle, cardiac muscle, and smooth muscle. Muscle tissue gives skeletal muscles the ability to muscle contra ...
cells, causing these tissues to remove glucose from the blood. When the blood sugar falls the pancreatic beta cells cease insulin production, but, instead, stimulate the neighboring pancreatic
alpha cells
Alpha cells (α-cells) are endocrine cells that are found in the Islets of Langerhans in the pancreas. Alpha cells secrete the peptide hormone glucagon in order to increase glucose levels in the blood stream.
Discovery
Islets of Langerhans we ...
to release
glucagon
Glucagon is a peptide hormone, produced by alpha cells of the pancreas. It raises the concentration of glucose and fatty acids in the bloodstream and is considered to be the main catabolic hormone of the body. It is also used as a Glucagon (medic ...
into the blood.
This, in turn, causes the liver to release glucose into the blood by breaking down stored
glycogen
Glycogen is a multibranched polysaccharide of glucose that serves as a form of energy storage in animals, fungi, and bacteria. It is the main storage form of glucose in the human body.
Glycogen functions as one of three regularly used forms ...
, and by means of gluconeogenesis. If the fall in the blood glucose level is particularly rapid or severe, other glucose sensors cause the release of
epinephrine
Adrenaline, also known as epinephrine, is a hormone and medication which is involved in regulating visceral functions (e.g., respiration). It appears as a white microcrystalline granule. Adrenaline is normally produced by the adrenal glands a ...
from the
adrenal glands
The adrenal glands (also known as suprarenal glands) are endocrine glands that produce a variety of hormones including adrenaline and the steroids aldosterone and cortisol. They are found above the kidneys. Each gland has an outer cortex which ...
into the blood. This has the same action as glucagon on glucose metabolism, but its effect is more pronounced.
In the liver glucagon and epinephrine cause the
phosphorylation
In biochemistry, phosphorylation is described as the "transfer of a phosphate group" from a donor to an acceptor. A common phosphorylating agent (phosphate donor) is ATP and a common family of acceptor are alcohols:
:
This equation can be writ ...
of the key, regulated enzymes of glycolysis,
fatty acid synthesis
In biochemistry, fatty acid synthesis is the creation of fatty acids from acetyl-CoA and NADPH through the action of enzymes. Two ''De novo synthesis, de novo'' fatty acid syntheses can be distinguished: cytosolic fatty acid synthesis (FAS/FASI) ...
,
cholesterol synthesis, gluconeogenesis, and glycogenolysis. Insulin has the opposite effect on these enzymes.
The phosphorylation and dephosphorylation of these enzymes (ultimately in response to the glucose level in the blood) is the dominant manner by which these pathways are controlled in the liver, fat, and muscle cells. Thus the phosphorylation of
phosphofructokinase inhibits glycolysis, whereas its dephosphorylation through the action of insulin stimulates glycolysis.
Regulated Enzymes in Glycolysis
The three
regulatory enzymes are
hexokinase
A hexokinase is an enzyme that irreversibly phosphorylates hexoses (six-carbon sugars), forming hexose phosphate. In most organisms, glucose is the most important substrate for hexokinases, and glucose-6-phosphate is the most important p ...
(or
glucokinase
Glucokinase () is an enzyme that facilitates phosphorylation of glucose to glucose-6-phosphate. Glucokinase is expressed in cells of the liver and pancreas of humans and most other vertebrates. In each of these organs it plays an important ro ...
in the liver),
phosphofructokinase, and
pyruvate kinase
Pyruvate kinase is the enzyme involved in the last step of glycolysis. It catalyzes the transfer of a phosphate group from phosphoenolpyruvate (PEP) to adenosine diphosphate (ADP), yielding one molecule of pyruvate and one molecule of ATP. Pyruv ...
. The
flux
Flux describes any effect that appears to pass or travel (whether it actually moves or not) through a surface or substance. Flux is a concept in applied mathematics and vector calculus which has many applications in physics. For transport phe ...
through the glycolytic pathway is adjusted in response to conditions both inside and outside the cell. The internal factors that regulate glycolysis do so primarily to provide
ATP in adequate quantities for the cell's needs. The external factors act primarily on the
liver
The liver is a major metabolic organ (anatomy), organ exclusively found in vertebrates, which performs many essential biological Function (biology), functions such as detoxification of the organism, and the Protein biosynthesis, synthesis of var ...
,
fat tissue
Adipose tissue (also known as body fat or simply fat) is a loose connective tissue composed mostly of adipocytes. It also contains the stromal vascular fraction (SVF) of cells including preadipocytes, fibroblasts, vascular endothelial cells and ...
, and
muscle
Muscle is a soft tissue, one of the four basic types of animal tissue. There are three types of muscle tissue in vertebrates: skeletal muscle, cardiac muscle, and smooth muscle. Muscle tissue gives skeletal muscles the ability to muscle contra ...
s, which can remove large quantities of glucose from the blood after meals (thus preventing
hyperglycemia
Hyperglycemia is a condition where unusually high amount of glucose is present in blood. It is defined as blood glucose level exceeding 6.9 mmol/L (125 mg/dL) after fasting for 8 hours or 10 mmol/L (180 mg/dL) 2 hours after eating.
Blood gluc ...
by storing the excess glucose as fat or glycogen, depending on the tissue type). The liver is also capable of releasing glucose into the blood between meals, during fasting, and exercise thus preventing
hypoglycemia
Hypoglycemia (American English), also spelled hypoglycaemia or hypoglycæmia (British English), sometimes called low blood sugar, is a fall in blood sugar to levels below normal, typically below 70 mg/dL (3.9 mmol/L). Whipple's tria ...
by means of
glycogenolysis
Glycogenolysis is the breakdown of glycogen (n) to glucose-1-phosphate and glycogen (n-1). Glycogen branches are catabolized by the sequential removal of glucose monomers via phosphorolysis, by the enzyme glycogen phosphorylase.
Mechanis ...
and
gluconeogenesis
Gluconeogenesis (GNG) is a metabolic pathway that results in the biosynthesis of glucose from certain non-carbohydrate carbon substrates. It is a ubiquitous process, present in plants, animals, fungi, bacteria, and other microorganisms. In verte ...
. These latter reactions coincide with the halting of glycolysis in the liver.
In addition hexokinase and
glucokinase
Glucokinase () is an enzyme that facilitates phosphorylation of glucose to glucose-6-phosphate. Glucokinase is expressed in cells of the liver and pancreas of humans and most other vertebrates. In each of these organs it plays an important ro ...
act independently of the hormonal effects as controls at the entry points of glucose into the cells of different tissues. Hexokinase responds to the
glucose-6-phosphate
Glucose 6-phosphate (G6P, sometimes called the Robison ester) is a glucose sugar phosphorylated at the hydroxy group on carbon 6. This dianion is very common in cells as the majority of glucose entering a cell will become phosphorylated in this wa ...
(G6P) level in the cell, or, in the case of glucokinase, to the blood sugar level in the blood to impart entirely intracellular controls of the glycolytic pathway in different tissues (see
below
Below may refer to:
*Earth
*Ground (disambiguation)
*Soil
*Floor
* Bottom (disambiguation)
*Less than
*Temperatures below freezing
*Hell or underworld
People with the surname
* Ernst von Below (1863–1955), German World War I general
* Fred Belo ...
).
When glucose has been converted into G6P by hexokinase or glucokinase, it can either be converted to
glucose-1-phosphate (G1P) for conversion to
glycogen
Glycogen is a multibranched polysaccharide of glucose that serves as a form of energy storage in animals, fungi, and bacteria. It is the main storage form of glucose in the human body.
Glycogen functions as one of three regularly used forms ...
, or it is alternatively converted by glycolysis to
pyruvate
Pyruvic acid (CH3COCOOH) is the simplest of the alpha-keto acids, with a carboxylic acid and a ketone functional group. Pyruvate, the conjugate base, CH3COCOO−, is an intermediate in several metabolic pathways throughout the cell.
Pyruvic ...
, which enters the
mitochondrion
A mitochondrion () is an organelle found in the cell (biology), cells of most eukaryotes, such as animals, plants and fungi. Mitochondria have a double lipid bilayer, membrane structure and use aerobic respiration to generate adenosine tri ...
where it is converted into
acetyl-CoA
Acetyl-CoA (acetyl coenzyme A) is a molecule that participates in many biochemical reactions in protein, carbohydrate and lipid metabolism. Its main function is to deliver the acetyl group to the citric acid cycle (Krebs cycle) to be oxidation, o ...
and then into
citrate
Citric acid is an organic compound with the formula . It is a colorless weak organic acid. It occurs naturally in citrus fruits. In biochemistry
Biochemistry, or biological chemistry, is the study of chemical processes within and relati ...
. Excess
citrate
Citric acid is an organic compound with the formula . It is a colorless weak organic acid. It occurs naturally in citrus fruits. In biochemistry
Biochemistry, or biological chemistry, is the study of chemical processes within and relati ...
is exported from the mitochondrion back into the cytosol, where
ATP citrate lyase regenerates
acetyl-CoA
Acetyl-CoA (acetyl coenzyme A) is a molecule that participates in many biochemical reactions in protein, carbohydrate and lipid metabolism. Its main function is to deliver the acetyl group to the citric acid cycle (Krebs cycle) to be oxidation, o ...
and
oxaloacetate
Oxaloacetic acid (also known as oxalacetic acid or OAA) is a crystalline organic compound with the chemical formula HO2CC(O)CH2CO2H. Oxaloacetic acid, in the form of its conjugate base oxaloacetate, is a metabolic intermediate in many processes ...
(OAA). The acetyl-CoA is then used for
fatty acid synthesis
In biochemistry, fatty acid synthesis is the creation of fatty acids from acetyl-CoA and NADPH through the action of enzymes. Two ''De novo synthesis, de novo'' fatty acid syntheses can be distinguished: cytosolic fatty acid synthesis (FAS/FASI) ...
and
cholesterol synthesis, two important ways of utilizing excess glucose when its concentration is high in blood. The regulated enzymes catalyzing these reactions perform these functions when they have been dephosphorylated through the action of insulin on the liver cells. Between meals, during
fasting
Fasting is the act of refraining from eating, and sometimes drinking. However, from a purely physiological context, "fasting" may refer to the metabolic status of a person who has not eaten overnight (before "breakfast"), or to the metabolic sta ...
,
exercise
Exercise or workout is physical activity that enhances or maintains fitness and overall health. It is performed for various reasons, including weight loss or maintenance, to aid growth and improve strength, develop muscles and the cardio ...
or hypoglycemia, glucagon and epinephrine are released into the blood. This causes liver glycogen to be converted back to G6P, and then converted to glucose by the liver-specific enzyme
glucose 6-phosphatase and released into the blood. Glucagon and epinephrine also stimulate gluconeogenesis, which converts non-carbohydrate substrates into G6P, which joins the G6P derived from glycogen, or substitutes for it when the liver glycogen store have been depleted. This is critical for brain function, since the brain utilizes glucose as an energy source under most conditions.
The simultaneously phosphorylation of, particularly,
phosphofructokinase, but also, to a certain extent pyruvate kinase, prevents glycolysis occurring at the same time as gluconeogenesis and glycogenolysis.
Hexokinase and glucokinase

All cells contain the enzyme
hexokinase
A hexokinase is an enzyme that irreversibly phosphorylates hexoses (six-carbon sugars), forming hexose phosphate. In most organisms, glucose is the most important substrate for hexokinases, and glucose-6-phosphate is the most important p ...
, which catalyzes the conversion of glucose that has entered the cell into
glucose-6-phosphate
Glucose 6-phosphate (G6P, sometimes called the Robison ester) is a glucose sugar phosphorylated at the hydroxy group on carbon 6. This dianion is very common in cells as the majority of glucose entering a cell will become phosphorylated in this wa ...
(G6P). Since the cell membrane is impervious to G6P, hexokinase essentially acts to transport glucose into the cells from which it can then no longer escape. Hexokinase is inhibited by high levels of G6P in the cell. Thus the rate of entry of glucose into cells partially depends on how fast G6P can be disposed of by glycolysis, and by
glycogen synthesis (in the cells which store glycogen, namely liver and muscles).
Glucokinase
Glucokinase () is an enzyme that facilitates phosphorylation of glucose to glucose-6-phosphate. Glucokinase is expressed in cells of the liver and pancreas of humans and most other vertebrates. In each of these organs it plays an important ro ...
, unlike hexokinase, is not inhibited by G6P. It occurs in liver cells, and will only phosphorylate the glucose entering the cell to form G6P, when the glucose in the blood is abundant. This being the first step in the glycolytic pathway in the liver, it therefore imparts an additional layer of control of the glycolytic pathway in this organ.
Phosphofructokinase
Phosphofructokinase is an important control point in the glycolytic pathway, since it is one of the irreversible steps and has key allosteric effectors,
AMP and
fructose 2,6-bisphosphate
Fructose 2,6-bisphosphate, abbreviated Fru-2,6-''P''2, is a metabolite that allosterically affects the activity of the enzymes phosphofructokinase 1 (PFK-1) and fructose 1,6-bisphosphatase (FBPase-1) to regulate glycolysis and gluconeogenesis. ...
(F2,6BP).
F2,6BP is a very potent activator of phosphofructokinase (PFK-1) that is synthesized when F6P is phosphorylated by a second phosphofructokinase (
PFK2). In the liver, when blood sugar is low and
glucagon
Glucagon is a peptide hormone, produced by alpha cells of the pancreas. It raises the concentration of glucose and fatty acids in the bloodstream and is considered to be the main catabolic hormone of the body. It is also used as a Glucagon (medic ...
elevates cAMP, PFK2 is phosphorylated by
protein kinase A
In cell biology, protein kinase A (PKA) is a family of serine-threonine kinases whose activity is dependent on cellular levels of cyclic AMP (cAMP). PKA is also known as cAMP-dependent protein kinase (). PKA has several functions in the cell, in ...
. The phosphorylation inactivates PFK2, and another domain on this protein becomes active as
fructose bisphosphatase-2, which converts F2,6BP back to F6P. Both
glucagon
Glucagon is a peptide hormone, produced by alpha cells of the pancreas. It raises the concentration of glucose and fatty acids in the bloodstream and is considered to be the main catabolic hormone of the body. It is also used as a Glucagon (medic ...
and
epinephrine
Adrenaline, also known as epinephrine, is a hormone and medication which is involved in regulating visceral functions (e.g., respiration). It appears as a white microcrystalline granule. Adrenaline is normally produced by the adrenal glands a ...
cause high levels of cAMP in the liver. The result of lower levels of liver F2,6BP is a decrease in activity of
phosphofructokinase and an increase in activity of
fructose 1,6-bisphosphatase, so that gluconeogenesis (in essence, "glycolysis in reverse") is favored. This is consistent with the role of the liver in such situations, since the response of the liver to these hormones is to release glucose to the blood.
ATP competes with AMP for the allosteric effector site on the PFK enzyme. ATP concentrations in cells are much higher than those of AMP, typically 100-fold higher, but the concentration of ATP does not change more than about 10% under physiological conditions, whereas a 10% drop in ATP results in a 6-fold increase in AMP. Thus, the relevance of ATP as an allosteric effector is questionable. An increase in AMP is a consequence of a decrease in
energy charge
The adenylate energy charge is an index used to measure the energy status of cell (biology), biological cells.
ATP or Mg-ATP is the principal molecule for storing and transferring energy in the cell : it is used for biosynthetic pathways, mainten ...
in the cell.
Citrate
Citric acid is an organic compound with the formula . It is a colorless weak organic acid. It occurs naturally in citrus fruits. In biochemistry
Biochemistry, or biological chemistry, is the study of chemical processes within and relati ...
inhibits phosphofructokinase when tested ''in vitro'' by enhancing the inhibitory effect of ATP. However, it is doubtful that this is a meaningful effect ''in vivo'', because citrate in the cytosol is utilized mainly for conversion to
acetyl-CoA
Acetyl-CoA (acetyl coenzyme A) is a molecule that participates in many biochemical reactions in protein, carbohydrate and lipid metabolism. Its main function is to deliver the acetyl group to the citric acid cycle (Krebs cycle) to be oxidation, o ...
for
fatty acid
In chemistry, in particular in biochemistry, a fatty acid is a carboxylic acid with an aliphatic chain, which is either saturated and unsaturated compounds#Organic chemistry, saturated or unsaturated. Most naturally occurring fatty acids have an ...
and
cholesterol
Cholesterol is the principal sterol of all higher animals, distributed in body Tissue (biology), tissues, especially the brain and spinal cord, and in Animal fat, animal fats and oils.
Cholesterol is biosynthesis, biosynthesized by all anima ...
synthesis.
TIGAR, a p53 induced enzyme, is responsible for the regulation of
phosphofructokinase and acts to protect against oxidative stress. TIGAR is a single enzyme with dual function that regulates F2,6BP. It can behave as a phosphatase (fructuose-2,6-bisphosphatase) which cleaves the phosphate at carbon-2 producing F6P. It can also behave as a kinase (PFK2) adding a phosphate onto carbon-2 of F6P which produces F2,6BP. In humans, the TIGAR protein is encoded by ''C12orf5'' gene. The TIGAR enzyme will hinder the forward progression of glycolysis, by creating a build up of fructose-6-phosphate (F6P) which is isomerized into glucose-6-phosphate (G6P). The accumulation of G6P will shunt carbons into the pentose phosphate pathway.
Pyruvate kinase

The final step of glycolysis is catalysed by pyruvate kinase to form pyruvate and another ATP. It is regulated by a range of different transcriptional, covalent and non-covalent regulation mechanisms, which can vary widely in different tissues. For example, in the liver, pyruvate kinase is regulated based on glucose availability. During fasting (no glucose available),
glucagon
Glucagon is a peptide hormone, produced by alpha cells of the pancreas. It raises the concentration of glucose and fatty acids in the bloodstream and is considered to be the main catabolic hormone of the body. It is also used as a Glucagon (medic ...
activates
protein kinase A
In cell biology, protein kinase A (PKA) is a family of serine-threonine kinases whose activity is dependent on cellular levels of cyclic AMP (cAMP). PKA is also known as cAMP-dependent protein kinase (). PKA has several functions in the cell, in ...
which phosphorylates pyruvate kinase to inhibit it.
An increase in blood sugar leads to secretion of
insulin
Insulin (, from Latin ''insula'', 'island') is a peptide hormone produced by beta cells of the pancreatic islets encoded in humans by the insulin (''INS)'' gene. It is the main Anabolism, anabolic hormone of the body. It regulates the metabol ...
, which activates
protein phosphatase 1
Protein phosphatase 1 (PP1) belongs to a certain class of phosphatases known as protein serine/threonine phosphatases. This type of phosphatase includes metal-dependent protein phosphatases (PPMs) and aspartate-based phosphatases. PP1 has been fo ...
, leading to dephosphorylation and re-activation of pyruvate kinase.
These controls prevent pyruvate kinase from being active at the same time as the enzymes that catalyze the reverse reaction (
pyruvate carboxylase
Pyruvate carboxylase (PC) encoded by the gene PC is an enzyme () of the ligase class that catalyzes (depending on the species) the physiologically irreversible carboxylation of pyruvate to form oxaloacetate (OAA).
Image:Pyruvic-acid-2D-ske ...
and
phosphoenolpyruvate carboxykinase
Phosphoenolpyruvate carboxykinase (, PEPCK) is an enzyme in the lyase family used in the metabolic pathway of gluconeogenesis. It converts oxaloacetate into phosphoenolpyruvate and carbon dioxide.
It is found in two forms, cytosolic and mitoc ...
), preventing a
futile cycle.
Conversely, the isoform of pyruvate kinasein found in muscle is not affected by protein kinase A (which is activated by adrenaline in that tissue), so that glycolysis remains active in muscles even during fasting.
Post-glycolysis processes
The overall process of glycolysis is:
:Glucose + 2 NAD
+ + 2 ADP + 2 P
i → 2 Pyruvate + 2 NADH + 2 H
+ + 2 ATP + 2 H
2O
If glycolysis were to continue indefinitely, all of the NAD
+ would be used up, and glycolysis would stop. To allow glycolysis to continue, organisms must be able to oxidize NADH back to NAD
+. How this is performed depends on which external electron acceptor is available.
Anoxic regeneration of NAD+
One method of doing this is to simply have the pyruvate do the oxidation; in this process, pyruvate is converted to
lactate (the
conjugate base
A conjugate acid, within the Brønsted–Lowry acid–base theory, is a chemical compound formed when an acid gives a proton () to a base—in other words, it is a base with a hydrogen ion added to it, as it loses a hydrogen ion in the reve ...
of lactic acid) in a process called
lactic acid fermentation
Lactic acid fermentation is a metabolic process by which glucose or other hexose, six-carbon sugars (also, disaccharides of six-carbon sugars, e.g. sucrose or lactose) are converted into cellular energy and the metabolite lactic acid, lactate, w ...
:
:Pyruvate + NADH + H
+ → Lactate + NAD
+
This process occurs in the
bacteria
Bacteria (; : bacterium) are ubiquitous, mostly free-living organisms often consisting of one Cell (biology), biological cell. They constitute a large domain (biology), domain of Prokaryote, prokaryotic microorganisms. Typically a few micr ...
involved in making
yogurt
Yogurt (; , from , ; also spelled yoghurt, yogourt or yoghourt) is a food produced by bacterial Fermentation (food), fermentation of milk. Fermentation of sugars in the milk by these bacteria produces lactic acid, which acts on milk protein to ...
(the lactic acid causes the milk to curdle). This process also occurs in animals under hypoxic (or partially anaerobic) conditions, found, for example, in overworked muscles that are starved of oxygen. In many tissues, this is a cellular last resort for energy; most animal tissue cannot tolerate anaerobic conditions for an extended period of time.
Some organisms, such as yeast, convert NADH back to NAD
+ in a process called
ethanol fermentation
Ethanol fermentation, also called alcoholic fermentation, is a biological process which converts sugars such as glucose, fructose, and sucrose into cellular energy, producing ethanol and carbon dioxide as by-products. Because yeasts perform this ...
. In this process, the pyruvate is converted first to acetaldehyde and carbon dioxide, and then to ethanol.
Lactic acid fermentation and ethanol fermentation can occur in the absence of oxygen. This anaerobic fermentation allows many single-cell organisms to use glycolysis as their only energy source.
Anoxic regeneration of NAD
+ is only an effective means of energy production during short, intense exercise in vertebrates, for a period ranging from 10 seconds to 2 minutes during a maximal effort in humans. (At lower exercise intensities it can sustain muscle activity in
diving animals, such as seals, whales and other aquatic vertebrates, for very much longer periods of time.) Under these conditions NAD
+ is replenished by NADH donating its electrons to pyruvate to form lactate. This produces 2 ATP molecules per glucose molecule, or about 5% of glucose's energy potential (38 ATP molecules in bacteria). But the speed at which ATP is produced in this manner is about 100 times that of oxidative phosphorylation. The pH in the cytoplasm quickly drops when hydrogen ions accumulate in the muscle, eventually inhibiting the enzymes involved in glycolysis.
The burning sensation in muscles during hard exercise can be attributed to the release of hydrogen ions during the shift to glucose fermentation from glucose oxidation to carbon dioxide and water, when aerobic metabolism can no longer keep pace with the energy demands of the muscles. These hydrogen ions form a part of lactic acid. The body falls back on this less efficient but faster method of producing ATP under low oxygen conditions. This is thought to have been the primary means of energy production in earlier organisms before oxygen reached high concentrations in the atmosphere between 2000 and 2500 million years ago, and thus would represent a more ancient form of energy production than the aerobic replenishment of NAD
+ in cells.
The liver in mammals gets rid of this excess lactate by transforming it back into pyruvate under aerobic conditions; see
Cori cycle
The Cori cycle (also known as the lactic acid cycle), named after its discoverers, Carl Ferdinand Cori and Gerty Cori, is a metabolic pathway in which lactic acid, lactate, produced by anaerobic glycolysis in muscles, is transported to the liver ...
.
Fermentation of pyruvate to lactate is sometimes also called "anaerobic glycolysis", however, glycolysis ends with the production of pyruvate regardless of the presence or absence of oxygen.
In the above two examples of fermentation, NADH is oxidized by transferring two electrons to pyruvate. However, anaerobic bacteria use a wide variety of compounds as the terminal electron acceptors in
cellular respiration
Cellular respiration is the process of oxidizing biological fuels using an inorganic electron acceptor, such as oxygen, to drive production of adenosine triphosphate (ATP), which stores chemical energy in a biologically accessible form. Cell ...
: nitrogenous compounds, such as nitrates and nitrites; sulfur compounds, such as sulfates, sulfites, sulfur dioxide, and elemental sulfur; carbon dioxide; iron compounds; manganese compounds; cobalt compounds; and uranium compounds.
Aerobic regeneration of NAD+ and further catabolism of pyruvate
In
aerobic eukaryote
The eukaryotes ( ) constitute the Domain (biology), domain of Eukaryota or Eukarya, organisms whose Cell (biology), cells have a membrane-bound cell nucleus, nucleus. All animals, plants, Fungus, fungi, seaweeds, and many unicellular organisms ...
s, a complex mechanism has developed to use the oxygen in air as the final electron acceptor, in a process called
oxidative phosphorylation
Oxidative phosphorylation(UK , US : or electron transport-linked phosphorylation or terminal oxidation, is the metabolic pathway in which Cell (biology), cells use enzymes to Redox, oxidize nutrients, thereby releasing chemical energy in order ...
.
Aerobic prokaryotes
A prokaryote (; less commonly spelled procaryote) is a single-celled organism whose cell lacks a nucleus and other membrane-bound organelles. The word ''prokaryote'' comes from the Ancient Greek (), meaning 'before', and (), meaning 'nut' ...
, which lack mitochondria, use a variety of
simpler mechanisms.
* Firstly, the
NADH + H+ generated by glycolysis has to be transferred to the mitochondrion to be oxidized, and thus to regenerate the NAD
+ necessary for glycolysis to continue. However the inner mitochondrial membrane is impermeable to NADH and NAD
+.
Use is therefore made of two "shuttles" to transport the electrons from NADH across the mitochondrial membrane. They are the
malate-aspartate shuttle and the
glycerol phosphate shuttle. In the former the electrons from NADH are transferred to cytosolic
oxaloacetate
Oxaloacetic acid (also known as oxalacetic acid or OAA) is a crystalline organic compound with the chemical formula HO2CC(O)CH2CO2H. Oxaloacetic acid, in the form of its conjugate base oxaloacetate, is a metabolic intermediate in many processes ...
to form
malate
Malic acid is an organic compound with the molecular formula . It is a dicarboxylic acid that is made by all living organisms, contributes to the sour taste of fruits, and is used as a food additive. Malic acid has two stereoisomeric forms ( ...
. The malate then traverses the inner mitochondrial membrane into the mitochondrial matrix, where it is reoxidized by NAD
+ forming intra-mitochondrial oxaloacetate and NADH. The oxaloacetate is then re-cycled to the cytosol via its conversion to aspartate which is readily transported out of the mitochondrion. In the glycerol phosphate shuttle electrons from cytosolic NADH are transferred to
dihydroxyacetone
Dihydroxyacetone (; DHA), also known as glycerone, is a simple saccharide (a triose) with formula .
DHA is primarily used as an ingredient in sunless tanning products. It is often derived from plant sources such as sugar beets and sugar cane, ...
to form
glycerol-3-phosphate which readily traverses the outer mitochondrial membrane. Glycerol-3-phosphate is then reoxidized to dihydroxyacetone, donating its electrons to
FAD
A fad, trend, or craze is any form of collective behavior that develops within a culture, a generation, or social group in which a group of people enthusiastically follow an impulse for a short time period.
Fads are objects or behaviors tha ...
instead of NAD
+.
This reaction takes place on the inner mitochondrial membrane, allowing FADH
2 to donate its electrons directly to coenzyme Q (
ubiquinone
Coenzyme Q10 (CoQ10 ), also known as ubiquinone, is a naturally occurring Cofactor (biochemistry), biochemical cofactor (coenzyme) and an antioxidant produced by the human body. It can also be obtained from dietary sources, such as meat, fish, ...
) which is part of the
electron transport chain
An electron transport chain (ETC) is a series of protein complexes and other molecules which transfer electrons from electron donors to electron acceptors via redox reactions (both reduction and oxidation occurring simultaneously) and couples th ...
which ultimately transfers electrons to molecular oxygen , with the formation of water, and the release of energy eventually captured in the form of
ATP.
* The glycolytic end-product, pyruvate (plus NAD
+) is converted to
acetyl-CoA
Acetyl-CoA (acetyl coenzyme A) is a molecule that participates in many biochemical reactions in protein, carbohydrate and lipid metabolism. Its main function is to deliver the acetyl group to the citric acid cycle (Krebs cycle) to be oxidation, o ...
, and NADH + H
+ within the
mitochondria
A mitochondrion () is an organelle found in the cells of most eukaryotes, such as animals, plants and fungi. Mitochondria have a double membrane structure and use aerobic respiration to generate adenosine triphosphate (ATP), which is us ...
in a process called
pyruvate decarboxylation.
* The resulting acetyl-CoA enters the
citric acid cycle
The citric acid cycle—also known as the Krebs cycle, Szent–Györgyi–Krebs cycle, or TCA cycle (tricarboxylic acid cycle)—is a series of chemical reaction, biochemical reactions that release the energy stored in nutrients through acetyl-Co ...
(or Krebs Cycle), where the acetyl group of the acetyl-CoA is converted into carbon dioxide by two decarboxylation reactions with the formation of yet more intra-mitochondrial NADH + H
+.
* The intra-mitochondrial NADH + H
+ is oxidized to NAD
+ by the
electron transport chain
An electron transport chain (ETC) is a series of protein complexes and other molecules which transfer electrons from electron donors to electron acceptors via redox reactions (both reduction and oxidation occurring simultaneously) and couples th ...
, using oxygen as the final electron acceptor to form water. The energy released during this process is used to create a hydrogen ion (or proton) gradient across the
inner membrane of the mitochondrion
The inner mitochondrial membrane (IMM) is the mitochondrial membrane which separates the mitochondrial matrix from the intermembrane space.
Structure
The structure of the inner mitochondrial membrane is extensively folded and compartmentalized. T ...
.
* Finally, the proton gradient is used to produce about 2.5
ATP for every NADH + H
+ oxidized in a process called
oxidative phosphorylation
Oxidative phosphorylation(UK , US : or electron transport-linked phosphorylation or terminal oxidation, is the metabolic pathway in which Cell (biology), cells use enzymes to Redox, oxidize nutrients, thereby releasing chemical energy in order ...
.
Conversion of carbohydrates into fatty acids and cholesterol
The pyruvate produced by glycolysis is an important intermediary in the conversion of carbohydrates into
fatty acids
In chemistry, in particular in biochemistry, a fatty acid is a carboxylic acid with an aliphatic chain, which is either saturated or unsaturated. Most naturally occurring fatty acids have an unbranched chain of an even number of carbon atoms, ...
and
cholesterol
Cholesterol is the principal sterol of all higher animals, distributed in body Tissue (biology), tissues, especially the brain and spinal cord, and in Animal fat, animal fats and oils.
Cholesterol is biosynthesis, biosynthesized by all anima ...
.
This occurs via the conversion of pyruvate into
acetyl-CoA
Acetyl-CoA (acetyl coenzyme A) is a molecule that participates in many biochemical reactions in protein, carbohydrate and lipid metabolism. Its main function is to deliver the acetyl group to the citric acid cycle (Krebs cycle) to be oxidation, o ...
in the
mitochondrion
A mitochondrion () is an organelle found in the cell (biology), cells of most eukaryotes, such as animals, plants and fungi. Mitochondria have a double lipid bilayer, membrane structure and use aerobic respiration to generate adenosine tri ...
. However, this acetyl CoA needs to be transported into cytosol where the synthesis of fatty acids and cholesterol occurs. This cannot occur directly. To obtain cytosolic acetyl-CoA,
citrate
Citric acid is an organic compound with the formula . It is a colorless weak organic acid. It occurs naturally in citrus fruits. In biochemistry
Biochemistry, or biological chemistry, is the study of chemical processes within and relati ...
(produced by the condensation of acetyl CoA with
oxaloacetate
Oxaloacetic acid (also known as oxalacetic acid or OAA) is a crystalline organic compound with the chemical formula HO2CC(O)CH2CO2H. Oxaloacetic acid, in the form of its conjugate base oxaloacetate, is a metabolic intermediate in many processes ...
) is removed from the
citric acid cycle
The citric acid cycle—also known as the Krebs cycle, Szent–Györgyi–Krebs cycle, or TCA cycle (tricarboxylic acid cycle)—is a series of chemical reaction, biochemical reactions that release the energy stored in nutrients through acetyl-Co ...
and carried across the inner mitochondrial membrane into the
cytosol
The cytosol, also known as cytoplasmic matrix or groundplasm, is one of the liquids found inside cells ( intracellular fluid (ICF)). It is separated into compartments by membranes. For example, the mitochondrial matrix separates the mitochondri ...
.
There it is cleaved by
ATP citrate lyase into acetyl-CoA and oxaloacetate. The oxaloacetate is returned to mitochondrion as malate (and then back into oxaloacetate to transfer more acetyl-CoA out of the mitochondrion). The cytosolic acetyl-CoA can be carboxylated by
acetyl-CoA carboxylase
Acetyl-CoA carboxylase (ACC) is a biotin-dependent enzyme () that catalyzes the irreversible carboxylation of acetyl-CoA to produce malonyl-CoA through its two catalytic activities, biotin carboxylase (BC) and carboxyltransferase (CT). ACC ...
into
malonyl CoA, the first committed step in the
synthesis of fatty acids, or it can be combined with
acetoacetyl-CoA to form 3-hydroxy-3-methylglutaryl-CoA (
HMG-CoA
β-Hydroxy β-methylglutaryl-CoA (HMG-CoA), also known as 3-hydroxy-3-methylglutaryl coenzyme A, is an intermediate in the mevalonate pathway, mevalonate and ketogenesis pathways. It is formed from acetyl CoA and acetoacetyl CoA by HMG-CoA synthase ...
) which is the rate limiting step controlling the
synthesis of cholesterol.
Cholesterol can be used as is, as a structural component of cellular membranes, or it can be used to synthesize the
steroid hormones,
bile salts
Bile acids are steroid acids found predominantly in the bile of mammals and other vertebrates. Diverse bile acids are synthesized in the liver in peroxisomes. Bile acids are conjugated with taurine or glycine residues to give anions called bile ...
, and
vitamin D
Vitamin D is a group of structurally related, fat-soluble compounds responsible for increasing intestinal absorption of calcium, magnesium, and phosphate, along with numerous other biological functions. In humans, the most important compo ...
.
Conversion of pyruvate into oxaloacetate for the citric acid cycle
Pyruvate molecules produced by glycolysis are
actively transported across the inner
mitochondrial
A mitochondrion () is an organelle found in the cells of most eukaryotes, such as animals, plants and fungi. Mitochondria have a double membrane structure and use aerobic respiration to generate adenosine triphosphate (ATP), which is used ...
membrane, and into the matrix where they can either be
oxidized
Redox ( , , reduction–oxidation or oxidation–reduction) is a type of chemical reaction in which the oxidation states of the reactants change. Oxidation is the loss of electrons or an increase in the oxidation state, while reduction is ...
and combined with
coenzyme A
Coenzyme A (CoA, SHCoA, CoASH) is a coenzyme, notable for its role in the Fatty acid metabolism#Synthesis, synthesis and Fatty acid metabolism#.CE.B2-Oxidation, oxidation of fatty acids, and the oxidation of pyruvic acid, pyruvate in the citric ac ...
to form , acetyl-CoA, and NADH,
or they can be
carboxylated (by
pyruvate carboxylase
Pyruvate carboxylase (PC) encoded by the gene PC is an enzyme () of the ligase class that catalyzes (depending on the species) the physiologically irreversible carboxylation of pyruvate to form oxaloacetate (OAA).
Image:Pyruvic-acid-2D-ske ...
) to form
oxaloacetate
Oxaloacetic acid (also known as oxalacetic acid or OAA) is a crystalline organic compound with the chemical formula HO2CC(O)CH2CO2H. Oxaloacetic acid, in the form of its conjugate base oxaloacetate, is a metabolic intermediate in many processes ...
. This latter reaction "fills up" the amount of oxaloacetate in the citric acid cycle, and is therefore an
anaplerotic reaction (from the Greek meaning to "fill up"), increasing the cycle's capacity to metabolize acetyl-CoA when the tissue's energy needs (e.g. in
heart
The heart is a muscular Organ (biology), organ found in humans and other animals. This organ pumps blood through the blood vessels. The heart and blood vessels together make the circulatory system. The pumped blood carries oxygen and nutrie ...
and
skeletal muscle
Skeletal muscle (commonly referred to as muscle) is one of the three types of vertebrate muscle tissue, the others being cardiac muscle and smooth muscle. They are part of the somatic nervous system, voluntary muscular system and typically are a ...
) are suddenly increased by activity.
In the
citric acid cycle
The citric acid cycle—also known as the Krebs cycle, Szent–Györgyi–Krebs cycle, or TCA cycle (tricarboxylic acid cycle)—is a series of chemical reaction, biochemical reactions that release the energy stored in nutrients through acetyl-Co ...
all the intermediates (e.g. citrate, iso-citrate, alpha-ketoglutarate, succinate, fumarate, malate and oxaloacetate) are regenerated during each turn of the cycle. Adding more of any of these intermediates to the mitochondrion therefore means that that additional amount is retained within the cycle, increasing all the other intermediates as one is converted into the other. Hence the addition of oxaloacetate greatly increases the amounts of all the citric acid intermediates, thereby increasing the cycle's capacity to metabolize acetyl CoA, converting its acetate component into and water, with the release of enough energy to form 11
ATP and 1
GTP molecule for each additional molecule of acetyl CoA that combines with oxaloacetate in the cycle.
To cataplerotically remove oxaloacetate from the citric cycle,
malate
Malic acid is an organic compound with the molecular formula . It is a dicarboxylic acid that is made by all living organisms, contributes to the sour taste of fruits, and is used as a food additive. Malic acid has two stereoisomeric forms ( ...
can be transported from the mitochondrion into the cytoplasm, decreasing the amount of oxaloacetate that can be regenerated.
Furthermore, citric acid intermediates are
constantly used to form a variety of substances such as the purines, pyrimidines and porphyrins.
Intermediates for other pathways
This article concentrates on the
catabolic
Catabolism () is the set of metabolic pathways that breaks down molecules into smaller units that are either oxidized to release energy or used in other anabolic reactions. Catabolism breaks down large molecules (such as polysaccharides, lipi ...
role of glycolysis with regard to converting potential chemical energy to usable chemical energy during the oxidation of glucose to pyruvate. Many of the metabolites in the glycolytic pathway are also used by
anabolic
Anabolism () is the set of metabolic pathways that construct macromolecules like DNA or RNA from smaller units. These reactions require energy, known also as an endergonic process. Anabolism is the building-up aspect of metabolism, whereas catab ...
pathways, and, as a consequence, flux through the pathway is critical to maintain a supply of carbon skeletons for biosynthesis.
The following metabolic pathways are all strongly reliant on glycolysis as a source of metabolites: and many more.
*
Pentose phosphate pathway
The pentose phosphate pathway (also called the phosphogluconate pathway and the hexose monophosphate shunt or HMP shunt) is a metabolic pathway parallel to glycolysis. It generates NADPH and pentoses (five-carbon sugars) as well as ribose 5-ph ...
, which begins with the dehydrogenation of
glucose-6-phosphate
Glucose 6-phosphate (G6P, sometimes called the Robison ester) is a glucose sugar phosphorylated at the hydroxy group on carbon 6. This dianion is very common in cells as the majority of glucose entering a cell will become phosphorylated in this wa ...
, the first intermediate to be produced by glycolysis, produces various pentose sugars, and
NADPH
Nicotinamide adenine dinucleotide phosphate, abbreviated NADP or, in older notation, TPN (triphosphopyridine nucleotide), is a cofactor used in anabolic reactions, such as the Calvin cycle and lipid and nucleic acid syntheses, which require N ...
for the synthesis of
fatty acid
In chemistry, in particular in biochemistry, a fatty acid is a carboxylic acid with an aliphatic chain, which is either saturated and unsaturated compounds#Organic chemistry, saturated or unsaturated. Most naturally occurring fatty acids have an ...
s and
cholesterol
Cholesterol is the principal sterol of all higher animals, distributed in body Tissue (biology), tissues, especially the brain and spinal cord, and in Animal fat, animal fats and oils.
Cholesterol is biosynthesis, biosynthesized by all anima ...
.
*
Glycogen synthesis also starts with glucose-6-phosphate at the beginning of the glycolytic pathway.
*
Glycerol
Glycerol () is a simple triol compound. It is a colorless, odorless, sweet-tasting, viscous liquid. The glycerol backbone is found in lipids known as glycerides. It is also widely used as a sweetener in the food industry and as a humectant in pha ...
, for the formation of
triglyceride
A triglyceride (from '' tri-'' and '' glyceride''; also TG, triacylglycerol, TAG, or triacylglyceride) is an ester derived from glycerol and three fatty acids.
Triglycerides are the main constituents of body fat in humans and other vertebrates ...
s and
phospholipid
Phospholipids are a class of lipids whose molecule has a hydrophilic "head" containing a phosphate group and two hydrophobic "tails" derived from fatty acids, joined by an alcohol residue (usually a glycerol molecule). Marine phospholipids typ ...
s, is produced from the glycolytic intermediate
glyceraldehyde-3-phosphate.
* Various post-glycolytic pathways:
:*
Fatty acid synthesis
In biochemistry, fatty acid synthesis is the creation of fatty acids from acetyl-CoA and NADPH through the action of enzymes. Two ''De novo synthesis, de novo'' fatty acid syntheses can be distinguished: cytosolic fatty acid synthesis (FAS/FASI) ...
:*
Cholesterol synthesis
:* The
citric acid cycle
The citric acid cycle—also known as the Krebs cycle, Szent–Györgyi–Krebs cycle, or TCA cycle (tricarboxylic acid cycle)—is a series of chemical reaction, biochemical reactions that release the energy stored in nutrients through acetyl-Co ...
which in turn leads to:
::*
Amino acid synthesis
Amino acid biosynthesis is the set of biochemical processes (metabolic pathways) by which the amino acids are produced. The substrates for these processes are various compounds in the organism's diet or growth media. Not all organisms are able to ...
::*
Nucleotide synthesis
::*
Tetrapyrrole synthesis
Although
gluconeogenesis
Gluconeogenesis (GNG) is a metabolic pathway that results in the biosynthesis of glucose from certain non-carbohydrate carbon substrates. It is a ubiquitous process, present in plants, animals, fungi, bacteria, and other microorganisms. In verte ...
and glycolysis share many intermediates the one is not functionally a branch or tributary of the other. There are two regulatory steps in both pathways which, when active in the one pathway, are automatically inactive in the other. The two processes can therefore not be simultaneously active.
Indeed, if both sets of reactions were highly active at the same time the net result would be the hydrolysis of four high energy phosphate bonds (two ATP and two GTP) per reaction cycle.
NAD+ is the oxidizing agent in glycolysis, as it is in most other energy yielding metabolic reactions (e.g.
beta-oxidation
In biochemistry and metabolism, beta oxidation (also β-oxidation) is the Catabolism, catabolic process by which fatty acid molecules are broken down in the cytosol in prokaryotes and in the mitochondria in eukaryotes to generate acetyl-CoA. Acetyl ...
of fatty acids, and during the
citric acid cycle
The citric acid cycle—also known as the Krebs cycle, Szent–Györgyi–Krebs cycle, or TCA cycle (tricarboxylic acid cycle)—is a series of chemical reaction, biochemical reactions that release the energy stored in nutrients through acetyl-Co ...
). The NADH thus produced is primarily used to ultimately transfer electrons to to produce water, or, when is not available, to produce compounds such as
lactate or
ethanol
Ethanol (also called ethyl alcohol, grain alcohol, drinking alcohol, or simply alcohol) is an organic compound with the chemical formula . It is an Alcohol (chemistry), alcohol, with its formula also written as , or EtOH, where Et is the ps ...
(see ''Anoxic regeneration of NAD
+'' above). NADH is rarely used for synthetic processes, the notable exception being gluconeogenesis. During
fatty acid
In chemistry, in particular in biochemistry, a fatty acid is a carboxylic acid with an aliphatic chain, which is either saturated and unsaturated compounds#Organic chemistry, saturated or unsaturated. Most naturally occurring fatty acids have an ...
and
cholesterol synthesis the reducing agent is
NADPH
Nicotinamide adenine dinucleotide phosphate, abbreviated NADP or, in older notation, TPN (triphosphopyridine nucleotide), is a cofactor used in anabolic reactions, such as the Calvin cycle and lipid and nucleic acid syntheses, which require N ...
. This difference exemplifies a general principle that NADPH is consumed during biosynthetic reactions, whereas NADH is generated in energy-yielding reactions.
The source of the NADPH is two-fold. When
malate
Malic acid is an organic compound with the molecular formula . It is a dicarboxylic acid that is made by all living organisms, contributes to the sour taste of fruits, and is used as a food additive. Malic acid has two stereoisomeric forms ( ...
is oxidatively decarboxylated by "NADP
+-linked malic enzyme"
pyruvate
Pyruvic acid (CH3COCOOH) is the simplest of the alpha-keto acids, with a carboxylic acid and a ketone functional group. Pyruvate, the conjugate base, CH3COCOO−, is an intermediate in several metabolic pathways throughout the cell.
Pyruvic ...
, and NADPH are formed. NADPH is also formed by the
pentose phosphate pathway
The pentose phosphate pathway (also called the phosphogluconate pathway and the hexose monophosphate shunt or HMP shunt) is a metabolic pathway parallel to glycolysis. It generates NADPH and pentoses (five-carbon sugars) as well as ribose 5-ph ...
which converts glucose into ribose, which can be used in synthesis of
nucleotides
Nucleotides are Organic compound, organic molecules composed of a nitrogenous base, a pentose sugar and a phosphate. They serve as monomeric units of the nucleic acid polymers – deoxyribonucleic acid (DNA) and ribonucleic acid (RNA), both o ...
and
nucleic acids
Nucleic acids are large biomolecules that are crucial in all cells and viruses. They are composed of nucleotides, which are the monomer components: a 5-carbon sugar, a phosphate group and a nitrogenous base. The two main classes of nucleic a ...
, or it can be catabolized to pyruvate.
Glycolysis in disease
Diabetes
Cellular uptake of glucose occurs in response to insulin signals, and glucose is subsequently broken down through glycolysis, lowering blood sugar levels. However, insulin resistance or low insulin levels seen in diabetes result in hyperglycemia, where glucose levels in the blood rise and glucose is not properly taken up by cells. Hepatocytes further contribute to this hyperglycemia through
gluconeogenesis
Gluconeogenesis (GNG) is a metabolic pathway that results in the biosynthesis of glucose from certain non-carbohydrate carbon substrates. It is a ubiquitous process, present in plants, animals, fungi, bacteria, and other microorganisms. In verte ...
. Glycolysis in hepatocytes controls hepatic glucose production, and when glucose is overproduced by the liver without having a means of being broken down by the body, hyperglycemia results.
Genetic diseases
Glycolytic mutations are generally rare due to importance of the metabolic pathway; the majority of occurring mutations result in an inability of the cell to respire, and therefore cause the death of the cell at an early stage. However, some mutations (
glycogen storage disease
A glycogen storage disease (GSD, also glycogenosis and dextrinosis) is a metabolic disorder caused by a deficiency of an enzyme or transport protein affecting glycogen synthesis, glycogen breakdown, or glycolysis, glucose breakdown, typically in m ...
s and other
inborn errors of carbohydrate metabolism) are seen with one notable example being
pyruvate kinase deficiency
Pyruvate kinase deficiency is an inherited metabolic disorder of the enzyme pyruvate kinase which affects the survival of red blood cells. Both autosomal dominant and recessive inheritance have been observed with the disorder; classically, and mo ...
, leading to chronic hemolytic anemia.
In
combined malonic and methylmalonic aciduria (CMAMMA) due to
ACSF3 deficiency, glycolysis is reduced by −50%, which is caused by reduced
lipoylation of mitochondrial enzymes such as the
pyruvate dehydrogenase complex and
α-ketoglutarate dehydrogenase complex.
Cancer
Malignant tumor cells perform glycolysis at a rate that is ten times faster than their noncancerous tissue counterparts. During their genesis, limited capillary support often results in hypoxia (decreased O2 supply) within the tumor cells. Thus, these cells rely on anaerobic metabolic processes such as glycolysis for ATP (adenosine triphosphate). Some tumor cells overexpress specific glycolytic enzymes which result in higher rates of glycolysis. Often these enzymes are Isoenzymes, of traditional glycolysis enzymes, that vary in their susceptibility to traditional feedback inhibition. The increase in glycolytic activity ultimately counteracts the effects of hypoxia by generating sufficient ATP from this anaerobic pathway. This phenomenon was first described in 1930 by
Otto Warburg and is referred to as the
Warburg effect. The
Warburg hypothesis claims that cancer is primarily caused by dysfunctionality in mitochondrial metabolism, rather than because of the uncontrolled growth of cells.
A number of theories have been advanced to explain the Warburg effect. One such theory suggests that the increased glycolysis is a normal protective process of the body and that malignant change could be primarily caused by energy metabolism.
This high glycolysis rate has important medical applications, as high
aerobic glycolysis by malignant tumors is utilized clinically to diagnose and monitor treatment responses of
cancer
Cancer is a group of diseases involving Cell growth#Disorders, abnormal cell growth with the potential to Invasion (cancer), invade or Metastasis, spread to other parts of the body. These contrast with benign tumors, which do not spread. Po ...
s by
imaging
Imaging is the representation or reproduction of an object's form; especially a visual representation (i.e., the formation of an image).
Imaging technology is the application of materials and methods to create, preserve, or duplicate images.
...
uptake of
2-18F-2-deoxyglucose (FDG) (a
radioactive
Radioactive decay (also known as nuclear decay, radioactivity, radioactive disintegration, or nuclear disintegration) is the process by which an unstable atomic nucleus loses energy by radiation. A material containing unstable nuclei is conside ...
modified hexokinase
substrate
Substrate may refer to:
Physical layers
*Substrate (biology), the natural environment in which an organism lives, or the surface or medium on which an organism grows or is attached
** Substrate (aquatic environment), the earthy material that exi ...
) with
positron emission tomography
Positron emission tomography (PET) is a functional imaging technique that uses radioactive substances known as radiotracers to visualize and measure changes in metabolic processes, and in other physiological activities including blood flow, r ...
(PET).
There is ongoing research to affect mitochondrial metabolism and treat cancer by reducing glycolysis and thus starving cancerous cells in various new ways, including a
ketogenic diet
The ketogenic diet is a high-fat, adequate-protein, low-carbohydrate diet, low-carbohydrate dietary therapy that in conventional medicine is used mainly to treat hard-to-control (refractory) epilepsy in children. The diet forces the body to b ...
.
Interactive pathway map
The diagram below shows human protein names. Names in other organisms may be different and the number of
isozyme
In biochemistry, isozymes (also known as isoenzymes or more generally as multiple forms of enzymes) are enzymes that differ in amino acid sequence but catalyze the same chemical reaction. Isozymes usually have different kinetic parameters (e.g. di ...
s (such as HK1, HK2, ...) is likely to be different too.
Alternative nomenclature
Some of the metabolites in glycolysis have alternative names and nomenclature. In part, this is because some of them are common to other pathways, such as the
Calvin cycle
The Calvin cycle, light-independent reactions, bio synthetic phase, dark reactions, or photosynthetic carbon reduction (PCR) cycle of photosynthesis is a series of chemical reactions that convert carbon dioxide and hydrogen-carrier compounds into ...
.
Structure of glycolysis components in Fischer projections and polygonal model
The intermediates of glycolysis depicted in Fischer projections show the chemical changing step by step. Such image can be compared to polygonal model representation.
See also
*
Carbohydrate catabolism
*
Citric acid cycle
The citric acid cycle—also known as the Krebs cycle, Szent–Györgyi–Krebs cycle, or TCA cycle (tricarboxylic acid cycle)—is a series of chemical reaction, biochemical reactions that release the energy stored in nutrients through acetyl-Co ...
*
Cori cycle
The Cori cycle (also known as the lactic acid cycle), named after its discoverers, Carl Ferdinand Cori and Gerty Cori, is a metabolic pathway in which lactic acid, lactate, produced by anaerobic glycolysis in muscles, is transported to the liver ...
*
Fermentation (biochemistry)
Fermentation is a type of anaerobic metabolism which harnesses the redox potential of the reactants to make adenosine triphosphate (ATP) and organic end products. Organic molecules, such as glucose or other sugars, are catabolized and reduce ...
*
Gluconeogenesis
Gluconeogenesis (GNG) is a metabolic pathway that results in the biosynthesis of glucose from certain non-carbohydrate carbon substrates. It is a ubiquitous process, present in plants, animals, fungi, bacteria, and other microorganisms. In verte ...
*
Glycolytic oscillation
*
Glycogenoses (glycogen storage diseases)
*
Inborn errors of carbohydrate metabolism
*
Pentose phosphate pathway
The pentose phosphate pathway (also called the phosphogluconate pathway and the hexose monophosphate shunt or HMP shunt) is a metabolic pathway parallel to glycolysis. It generates NADPH and pentoses (five-carbon sugars) as well as ribose 5-ph ...
*
Pyruvate decarboxylation
*
Triose kinase
References
External links
A Detailed Glycolysis Animation providedby
IUBMBAdobe FlashRequired)
at RCSB PDB
Glycolytic cycle with animationsat wdv.com
Metabolism, Cellular Respiration and Photosynthesis – The Virtual Library of Biochemistry, Molecular Biology and Cell Biologyat ufp.pt
at
ExPASy
*
''metpath'': Interactive representation of glycolysis
{{Authority control
Biochemical reactions
Carbohydrates
Cellular respiration
Metabolic pathways